SUBCUTANEOUS INFLIXIMAB (CT-P13) AS MAINTENANCE THERAPY FOR CROHN'S DISEASE: A PHASE 3, RANDOMIZED, PLACEBO-CONTROLLED STUDY (LIBERTY-CD).

Background: After successful induction, a subset of patients with Crohn’s disease (CD) experience a secondary loss of response (LoR) to ustekinumab (UST) maintenance therapy. Dose intensification may assist in regaining response. The phase 3b randomized, double-blind, multicenter POWER study evaluated efficacy and safety of a single intravenous (IV) re-induction UST dose vs continued UST subcutaneous (SC) treatment in CD patients with LoR to standard UST every 8 weeks maintenance therapy.
Methods: Adults with moderately–severely active CD who initially responded to UST IV induction therapy per label and subsequently experienced LoR were included. LoR for inclusion was defined as CD activity index (CDAI) score of ≥220 and ≤450, in addition to elevated C-reactive protein (CRP; >3mg/L), fecal calprotectin (fCal; >250mg/kg) or endoscopy performed ≤3 months before Week (W)0 with evidence of active CD (≥1 ulcerations in the ileum and/or colon). At baseline (W0), randomized patients received either ~6mg/kg IV UST/SC placebo (IV arm), or IV placebo/SC UST 90mg (SC arm), followed by SC UST 90mg dosing in both groups at W8/16. Clinical and biomarker assessments were made at W0/8/16 and optional ileocolonoscopy at W0/16. Primary endpoint: clinical response (CRes; decrease of ≥100 points from W0/CDAI <150) at W16. Additional outcome measures included clinical, biomarker, endoscopic and quality of life endpoints assessed at W8/16.
Results: The analysis set comprised 215 patients at W0 (IV, n=108; SC, n=107). At W16, 92.6% and 86.0% completed treatment from IV and SC arms, respectively. In both arms (IV, 58.3%; SC, 57.9%) most patients experienced ≥2 biologic failures before initiating UST (Table 1). At W16, 49.1% in the IV arm and 37.4% in the SC arm achieved CRes (p=0.089). Percentages of patients with normalization of fCal, normalization of CRP and/or fCal, endoscopic remission and improvement, and improvement in IBDQ score were greater in the IV vs SC arm (Table 2). At W16, similar proportions of patients had ≥1 adverse event (AE) (IV, 60.2%; SC, 61.7%) and serious AEs (IV, 5.6%; SC, 5.6%). The proportions of patients with infections were similar between arms (IV, 23.1%; SC, 21.5%), with only 1 serious infection in each arm.
Conclusion: POWER is the first randomized, controlled, double-blind trial to assess the efficacy and safety of UST IV re-induction in patients with LoR during UST maintenance therapy. The CDAI-based primary endpoint at W16 was not met. However, patients in this heavily pre-treated population who received IV re-induction showed clinically meaningful improvements at W16 compared with those receiving SC, particularly for objective endpoints, including inflammatory biomarkers and endoscopic outcomes.

Background: CT-P13 subcutaneous (SC) infliximab formulation showed comparable efficacy and safety with CT-P13 intravenous (IV) infliximab in inflammatory bowel disease (IBD)¹ and rheumatoid arthritis². This study aimed to demonstrate the superiority of CT-P13 SC over placebo SC as maintenance therapy after induction therapy of CT-P13 IV in patients with Crohn’s disease (CD).

Methods: Moderately to severely active CD patients with Crohn’s disease activity index (CDAI) score 220 to 450 and simplified endoscopic activity score for Crohn’s disease (SES- CD) of ≥6 points for ileal-colonic CD or ≥4 points including ulcer score from at least 1 segment for ileal CD or colonic CD) were enrolled LIBERTY-CD study (NCT03945019) and treated with open-label CT-P13 IV 5 mg/kg at Weeks 0, 2 and 6 as induction therapy. At Week 10, patients who had a clinical response were randomized (2:1) to receive either CT-P13 SC 120 mg (CT-P13 SC) or placebo SC every 2 weeks up to Week 54. At Week 54, clinical remission and endoscopic response were assessed as co-primary endpoints. Clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission were assessed at Week 54 as key secondary endpoints. Safety was evaluated up to Week 54.

Results: A total of 396 patients were enrolled and 343 patients (86.6%) were randomized (231 in CT-P13 SC arm and 112 in placebo SC arm) at Week 10. At Week 54, the clinical remission rate was greater in CT-P13 SC arm than placebo SC arm (62.3% and 32.1% respectively, with P <0.0001). The endoscopic response rate was also greater in CT-P13 arm than placebo SC arm (51.1% and 17.9% respectively, with P <0.0001). CT-P13 SC also had significantly greater efficacy on key secondary endpoints results compared to placebo SC arm (Table 1). Safety profiles were generally comparable between CT-P13 SC and placebo SC arms, but a single death was reported during the maintenance phase (Table 2).

Conclusion: CT-P13 SC was more effective than placebo in clinical remission, endoscopic response, clinical response, clinical remission (alternative definition), endoscopic remission, and corticosteroid-free remission than placebo arm at Week 54. No new safety concerns were found during treatment of CT-P13 SC. These results demonstrate that maintenance therapy with CT-P13 SC could provide both a large clinical benefit and the convenience of SC administration to moderately to severely active CD patients.

REFERENCES:
[1] Schreiber et al., 2021. Gastroenterology 2021;160:2340–23
[2] Westhovens et al., 2020. Rheumatology 2020;00:1